Nilotinib in Patients (pts) with Philadelphia Chromosome-Positive (Ph+) Chronic Myelogenous Leukemia in Blast Crisis (CML-BC) Who Are Resistant or Intolerant to Imatinib.

Abstract

Background: Nilotinib is a novel orally active aminopyrimidine. It is a highly specific Bcr-Abl tyrosine kinase inhibitor (TKI) 30-fold more potent than imatinib. Based on the efficacy and favorable tolerability demonstrated by nilotinib in the phase I study, this phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in adult pts with Ph+ chronic myeloid leukemia in blast crisis (CML-BC) resistant to or intolerant of imatinib. The prognosis for these pts remains poor.Methods: The primary endpoint was confirmed hematologic response (HR). Imatinib resistance was defined as either treatment with imatinib >600 mg/day with disease progression, no HR in bone marrow after 4 weeks, or pts receiving <600 mg/day with mutations in any of the following amino acids: L248, G250, Q252, Y253, E255, T315, F317, or H396. Imatinib intolerance was defined as grade 3/4 adverse events, or grade 2 events persisting for >1 month while on imatinib. Nilotinib therapy was commenced at 400 mg twice daily (BID) with escalation to 600 mg BID for pts who had inadequate responses and no safety concerns.Results: Safety and efficacy data are reported for 135 BC (myeloid, n=103; lymphoid, n=29; unknown, n=3). The median age was 55 (18–79) years, the median time since CML diagnosis was 1.6 (<1–73) months, and 61.5% were men. 82% of the patients were imatinib-resistant and 18% were intolerant. Treatment with nilotinib is ongoing for 16 (12%) pts. The median treatment duration was 84 (3–485) days and the median average dose intensity was 800 mg/day. 119 (88%) pts discontinued treatment, of which 71 (53%) discontinued due to disease progression; 13 (10%) discontinued due to AEs. 38% of pts had >/=95% Ph+ metaphases at study entry. Chromosomal abnormalities other than Ph+ were also noted in 54% of pts at study entry. Extramedullary involvement was present in 39% of the pts. The most common Grade 3/4 hematologic laboratory abnormalities were neutropenia (67%), thrombocytopenia (62%), anemia (42%). The most common Grade 3/4 non- hematologic AEs were as follows: pneumonia (11%), pyrexia (7%), nausea (4%), diarrhea (4%), and asthenia (4%).Conclusions: Based on the CHR rates achieved in this very advanced patient population, nilotinib monotherapy appears to have clinical activity in pts with imatinib-resistant CML BC. Overall nilotinib is well tolerated in this patient population with advanced disease and with non-heme toxicity comparable to that observed for pts with CML-CP. The hematological responses were similar between myeloid and lymphoid Ph+ CML blast crises.Response for Patients With CML-BC With at Least 6 Months of Follow-upMyeloid (N = 103) n (%)Lymphoid (N = 29) n (%)Hematologic response40 (39)11 (38)CHR25 (24)8 (28)Marrow response5 (5)1 (3)Return to chronic phase10 (10)2 (7)SD31 (30)7 (24)PD18 (17)6 (21)Not evaluable5 (5)1 (3)Missing9 (9)4 (14)